Review Synthèse

Psoriasis and the new biologic agents: interrupting a T-AP dance

Scott R.A. Walsh, Neil H. Shear

Abstract corticosteroids, tar, anthralin, calcipotriol or tazarotene be- come cumbersome to apply as lesional surface area increases. IS AN IMMUNE-MEDIATED SKIN DISEASE in which chronic T- Furthermore, potential side effects of these therapies increase cell stimulation by -presenting cells (APC) occurs in the with the level of application. Nevertheless, topical treatment skin. This interplay between the T-cell and APC has been likened remains an adjunct in more severe disease to limit the re- to a “T-AP dance” where specific steps must occur in sequence to quirement for more aggressive therapies. Phototherapy is a result in T-cell activation and the disease phenotype; otherwise T- popular option in the treatment of more widespread disease. cell anergy would occur. Several novel engineered proteins de- However, ultraviolet light is generally only available in larger signed to block specific steps in immune activation (biologic treatment centres, requires a major time commitment (2–3 agents) have demonstrated efficacy in the treatment of psoriasis. times per week for many months) and can be associated with These agents include fusion proteins, monoclonal and an increased risk of cutaneous neoplasms.6 For moderate to recombinant cytokines. These act at specific steps during the T-AP dance either to inhibit T-cell activation, costimu- severe disease, oral systemic immunosuppressives such as lation and subsequent proliferation of T-cells, lead to immune de- and cyclosporine or oral retinoids are generally viation or induce specific cytokine blockades. The potential in- the mainstays of therapy. However, because of potentially creased selectivity for specific pathways in immune activation, widespread and possible hepatic or renal clinical efficacy and relative safety of these new agents offers an toxicities, the use of these agents is often limited. alternative for the treatment of moderate to severe psoriasis. Biologic agents are specifically engineered proteins de- signed to block particular immunologic activation steps in- CMAJ 2004;170(13):1933-41 volved in the pathogenesis of psoriasis. They may offer an- other treatment option for the 10%–35% of people with soriasis is a chronic T-lymphocyte (T-cell) mediated moderate to severe psoriasis. Although the various toxicities inflammatory immune skin disease affecting about of these agents are not yet completely known, it is hoped P 2% of children and adults.1,2 Classified among the that when geared to specific pathways in immune activation, papulosquamous diseases (scaling papules), psoriasis pre- these proteins may result in potentially less widespread im- sents as erythematous, hyperkeratotic, often pruritic, scal- munosuppression. They also may have less hepatic or renal ing papules and plaques (Fig. 1). Among the 4.5 million toxicity than presently available oral agents.7 Although the Americans afflicted with psoriasis, about 65% have mild great expense of these agents (about US$7000 to $20 000 disease (plaques covering less than 2% of the total body surface), 25% have moderate disease (2%–10% of the body area) and 10% have severe disease (> 10% of the body area).3 Although mild to moderate disease may be limited in area, disability can still be severe if the disease is visible on the face or limits mobility of the hands or feet. Psoriasis can dramatically affect psychosocial functioning with in- creased self-consciousness, frustration, depression, feelings of helplessness and suicidal thought.2 Author John Updike summarized his own battle with psoriasis: “My torture is skin deep … [W]e lepers live a long time … healthy in other respects … we hate to look upon ourselves. [T]he name of the disease … humiliation.”4,5 As psoriasis is a chronic relapsing disease, intermittent treatment may span a lifetime. In order to limit treatment toxicities, the most minimally toxic yet practical approach for the level of body coverage is chosen. An approach to the treatment of psoriasis is shown in Fig. 2. Although highly suc- Fig. 1: Widespread psoriasis. Well-demarcated erythematous

DOI:10.1503/cmaj.1031335 cessful in the treatment of mild disease, topical agents such as hyperkeratotic plaque with slight nonconfluent whitish scale.

CMAJ • JUNE 22, 2004; 170 (13) 1933

© 2004 Canadian Medical Association or its licensors Walsh and Shear

per year) may limit their general accessibility, they currently though initial T-AP interactions occur in lymph nodes (Fig. offer another treatment option for patients for whom sys- 5), ongoing T-AP interactions appear to subsequently occur temic immunosuppressives or phototherapy have failed, or in psoriatic plaques in the skin (Fig. 6).1 The activated T-cells where these treatments are contraindicated because of co- induce secondary hyperproliferation of epidermal, vascular morbid disease. Furthermore, some of these agents appear and occasionally synovial cells through the release of specific to have the potential for sustained clinical remissions, not cytokine mediators such as TNF-α and IFN-γ.1,9 generally seen with our current treatment choices.8 Initiation of the T-AP dance occurs when a specific T- cell receptor on a naïve (CD45 RA+) T-cell (CD4 or CD8) Immunobiology of skin encounters its specific processed antigen presented by the APC in the context of major histocompatibility complex Proinflammatory cytokines such as tumour necrosis fac- proteins (MHC II for exogenous interacting with tor-alpha (TNF-α) or -1 (IL-1) are not promi- CD4 T-cells or MHC I for endogenous antigens interact- nent in normal skin but can be produced by activated im- ing with CD8 T-cells). Although the nature of the initial mune cells or damaged keratinocytes. They signal the need stimulating antigen in psoriasis is not known, hypotheses for both a reparative and immunologic response (Fig. 3). include a molecular mimicry between streptococcal M pro- Fig. 4 depicts the initial generation of an immune re- teins and human keratins 6 and 17, or the aberrant self- sponse to any foreign antigen in the skin. Antigen-presenting presentation of cutaneous proteins.10,11 Without further cells (APC) mature upon capture of antigen and migrate to APC interaction, this initial interaction would lead to inac- the skin-draining lymph node, where they can activate anti- tivation of the T-cell (i.e., anergy). gen-specific naïve T-cells (see Fig. 5). The mature T-cells In order to prevent T-cell anergy, the APC has costimu- proliferate and express the skin-homing marker, cutaneous latory proteins on its surface that interact with specific T- lymphocyte-associated antigen, which can allow binding to cell proteins that have been up-regulated through T-cell re- the transmembrane endothelial cell adhesion molecules, E- ceptor antigen recognition (Figs. 5 and 7). These molecular and P-selectins. When the activated T-cells release cy- interactions activate the T-cells to become memory CD4 or tokines such as TNF-α and -gamma (IFN-γ), re- CD8 T-cells (CD45 R0+) and induce expression of CD2, generative responses can be initiated and other immune ef- IL-2 and IL-2 receptor (IL-2R or CD25). These latter mol- fector cells recruited, including neutrophils. ecules are necessary for subsequent T-cell proliferation and survival (Fig. 5). T-cells activated in skin-draining lymph The “T-AP” dance of psoriasis nodes also acquire cutaneous lymphocyte-associated anti- gen, which allows them to interact with E- and P-selectins Psoriasis is an inflammatory disorder where specific T-cell on the endothelial surfaces of the cutaneous vasculature, populations are stimulated by putative antigen presented by thus targeting them to sites of cutaneous inflammation. APC from the skin. Both helper-type T-cells (CD4) and cy- As T-cell activation occurs, 2 distinct lines of differentia- totoxic suppressor-type T-cells (CD8) are involved in psoria- tion are possible. Under the influence of IL-12 or IFN-γ, sis.1 This T-cell/APC (“T-AP”) interaction is much like a tap CD4 T-cells differentiate into a TH1 phenotype and CD8 dance where specific steps must occur in sequence to result in T-cells differentiate into a TC1 phenotype, both with ex- T-cell activation; otherwise T-cell anergy would occur. Al- pression of TNF-α, IL-2 and IFN-γ. This response is asso-

Biologic agents

Immunosuppressive agents (methotrexate, cyclosporine, etc.) and oral retinoids Phototherapy

Topical agents (corticosteroids, tar, anthralin, calcipotriol, tazarotene)

Mild Moderate Severe

Fig. 2: Approach to the treatment of psoriasis. Topical therapy alone is used to treat mild disease (< 2% of the total body surface area). It becomes adjunctive therapy in moderate (2%–10% of the surface area) and severe (> 10% of the surface area) dis- ease to limit the need for treatments that will be potentially more toxic to the patient. Phototherapy is an option for moderate to severe disease. Immunosuppressive agents and oral retinoids can be considered for widespread moderate and severe disease. The biologic agents represent a newer treatment option for people with this severity of disease. Severe disease also includes body areas that may be limited in extent, but result in functional limitations, such as hand and foot involvement.

1934 JAMC • 22 JUIN 2004; 170 (13) Psoriasis and the new biologics

ciated with increased cell-mediated immunity and diseases to present antigen. Instead, the psoriatic plaque begins to such as psoriasis. Alternatively, under the influence of IL-4 act as of a lymph node, with ongoing activation of T-cells or IL-10, CD-4 T-cells differentiate into a TH2 phenotype by APC in the skin itself. Keratinocytes also produce IL-8 and CD8 T-cells differentiate into a TC2 phenotype, both in response to TNF-α, which is chemotactic for neu- with expression of IL-4, IL-6, IL-10 and IL-11. This re- trophils. Movement of neutrophils and CD8 TC1 cells sponse is associated with production and allergic through the epidermis in conjunction with IFN-γ diseases such as atopic dermatitis (Fig. 5). The favoured dif- produced by activated T-cells and APC results in a regen- ferentiation pathway is determined by both the site of T-cell erative response by the keratinocytes with release of addi- activation and the cytokine profile released by the APC.1,12 tional proinflammatory cytokines, including IL-1 and IL- In psoriasis, activated CD4 memory T-cells localize to 6. The net result is increased proliferation and aberrant the dermis and activated CD8 memory T-cells localize to maturation of keratinocytes, manifested by elongation of the epidermis (Fig. 6). Production of inflammatory cy- the rete ridges, loss of the granular layer and parakeratosis tokines by these T-cells induces keratinocytes to express (retained nuclei in the stratum corneum) — the hallmarks intercellular adhesion molecule 1 (ICAM-1), CD40 and of psoriasis.1,7,12–14 MHC II, enabling further direct interactions between the keratinocyte and T-cells. TNF-α released from T-cells The new biologic agents: interrupting the T-AP also induces keratinocytes to produce vascular endothelial dance cell growth factor, resulting in neighbouring endothelial cell proliferation, expression of ICAM and vascular cell ad- The era of biological therapy began with early studies hesion molecules (VCAM) and further recruitment of acti- involving a , denileukin diftitox, which is vated T-cells into the skin through LFA-1. At this point, constructed by conjugating diphtheria toxin to soluble IL- mature APC no longer need to migrate to the lymph node 2. This approach effectively targeted activated T-cells and

+ Cytotoxic (CD45RO ) Langerhans + T-cell (CD 8 ) cell Epidermis Melanocyte

Keratinocyte

Memory T-cell + (CD45R0 ) Neutrophil Dermis Dermal dendritic cell Naive T-cells (CD4 & CD8) + CD45RA Endothelium Chesley Sheppard Fig. 3: Cellular players involved in generating immunological reactions in the skin. Langerhans’ cells and dermal dendritic cells are specialized antigen-presenting cells (APC) that sample antigen found in the epidermis and dermis, respectively. The majority of the T-cells in normal skin are found in the vasculature and deeper in the lymph nodes (not shown in figure) and represent naïve T-cells (marked by CD45RA+) that have not yet been stimulated to maturity by antigen presentation. Rare T-cells found in the der- mis and epidermis likely represent residual memory T-cells present from previous immune activation (these are CD45RO+). T- cells can be helper-type (CD4+) or cytotoxic, suppressor-type (CD8+). Neutrophils and other immune cells can be recruited from the blood vessels into the dermis in response to immune activation cues from endothelial cells, keratinocytes or T-cells.

CMAJ • JUNE 22, 2004; 170 (13) 1935 Walsh and Shear

improved psoriasis, but side effects of treatment, including backbone, or fully human. Humanized antibodies permit vascular leak syndrome, limited its application in cutaneous the most flexibility in design, generating minimal blocking disease. Nevertheless, targeting the T-cell was demon- of human antimurine antibodies. Fusion proteins are fully strated to improve psoriasis.15,16 human constructs often between the constant (Fc) portion The new biologic agents are recombinant proteins de- of an immunoglobulin molecule and the binding site of a re- signed to inhibit specific steps in the T-AP dance by block- ceptor (designated “-cept”). Finally, recombinant human cy- ing T-cell activation and costimulation and subsequent T- tokines can be used as treatment to modify the direction of cell proliferation or survival, altering the TH1/TC1 to a immune maturation. TH2/TC2 pathway (i.e., immune deviation), or blocking cytokine communication (Table 1 and Fig. 7). Nomencla- T-AP 1: blocking T-cell activation and ture for these new agents can be fairly confusing, but gener- costimulation ally reflects the delivery approach: antibody, fusion protein or cytokine.13,17 Monoclonal antibodies can be chimeric with The sequence of interactions between the T-cell and fused mouse and human segments (designated “-ximab”), APC has been the focus for development of the majority of humanized with intermittent murine sequences (designated the new biologic agents. Specific agents that interrupt the “-zumab”) or monkey sequences (primatized) in a human T-AP dance at this level of T-cell activation and APC cos-

Epidermis Langerhans 1 Cell Antigen 9 Cytokines IFN-γ TNF-α etc,

10 8 Antigen Endothelial lining 1 2 ICAM VCAM

E and P Neutrophil selectins Dermal Dermis 7 dendritic cell 3 6

CLA LFA-1 VLA-4 5 4 LYMPH NODE Antigen presentation to naive T-cells (CD45RA+) Mature activated T-cell (CD45RO+)

T-cell propagation and activation Chesley Sheppard Fig. 4: Initial generation of an immune response in skin. (1) Langerhans’ cells and dermal dendritic cells capture antigen. (2) While antigen is processed and presented on the surface of the APC, maturation occurs with the expression of costimulatory mol- ecules. (3) The APC migrate via the afferent lymphatics to the skin-draining lymph node. (4) In the lymph node, they present the processed antigen to naïve T-cells (CD45RA+) (Fig. 5) causing T-cell maturation, activation and proliferation. (5) Mature activated T-cells (CD45RO+) express CLA antigen. (6) CLA antigen is able to bind to E- and P-selectins expressed by endothelial cells in the dermis. (7) This interaction stimulates T-cells to express LFA-1 and VLA-4 and endothelial cells to produce intercellular and vas- cular adhesion molecules (ICAM and VCAM). (8) The interaction of these molecules allows the activated T-cells to migrate through the postcapillary venules into the dermis. (9) The activated T-cells can then migrate to areas of antigen expression in the dermis or epidermis. (10) The activated T-cell can secrete cytokines such as IFN-γ or TNF-α and recruit other immune effector cells, including neutrophils.

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timulation include , , , remissions of psoriasis obtained with single courses of ale- IDEC-114, CTLA4Ig, orthoclone and . facept treatment.8,18,19 Furthermore, the selectivity of this Fig. 7 diagrammatically demonstrates how alefacept, agent for activated memory T-cells via LFA-1/CD2 inter- siplizumab and efalizumab interrupt the T-AP dance. Ale- action limits the amount of global immunosuppression. facept is a fusion protein composed of the APC costimula- CD2 is also the target for the humanized monoclonal anti- tory molecule LFA-3 linked to the Fc portion of human body siplizumab. Binding of this antibody to CD2 on T-

IgG1. Binding of alefacept to CD2 previously up-regulated cells also prevents costimulation from LFA-3 on APC and on memory effector T-cells not only blocks necessary sig- may produce prolonged clinical remissions.20 nals for costimulation in the T-AP dance, but it also trig- Humanized monoclonal antibodies to other costimula- gers memory T-cell apoptosis through binding of the Fc tory molecules can also be used to block T-cell activation. portion of the fusion protein to receptors on natural killer Efalizumab, which binds to LFA-1 on T-cells, blocks APC cells.8,18 This reduction in activated memory T-cells appears interaction with ICAM-1, -2 and -3, and also may block T- to be responsible for the prolonged and sustained clinical cell migration into skin through similar receptors expressed

CLA

IL-2R 3 Cell mediated immunity TH1 (T-helper IL-2 IL-12 CD4+ cells ) IL-2R and autoimmune diseases IFN-γ IFN-γ such as rheumatoid 1 TNF-α arthritis and psoriasis

Antigen IL-2

CD3 MHC I/II TCR TC1 (Cytotoxic CD4/CD8 CD8+ cells) T-cell APC ICAM-1 LFA-1 CD45RO+ CD86 CTLA-4 CD80 CD28 LFA-3 CD2 CLA CD40 CD40L

2 TH2 (T-helper 4 IL-10 CD4+ cells ) Antibody production IL-4 IL-4 and antibody-mediated IL-6 autoimmune diseases IL-10 such as atopic dermatitis CD8 +

TC2 (Cytotoxic CD8+ cells) Chesley Sheppard Fig. 5: Stimulation of naïve T-cells by activated APC in the skin-draining lymph node. (1) Naïve T-cells (CD45RA+) can be either CD4+ (T-helper cells) or CD8+ (cytotoxic, suppressor) and recognize antigen presented by APC in the context of major histocom- patibility complex (MHC) proteins II or I, respectively. (2) Costimulatory molecules induced on the T-cells by this interaction with APC (the T-AP dance) include LFA-1, CTLA-4, CD28, CD2 and CD40 ligand. These bind to upregulated costimulatory molecules on the APC which include ICAM-1, CD86, CD80, LFA-3 and CD40. Without costimulatory molecular interactions, binding of the T-cell receptor with MHC-presented antigen by the APC would result in T-cell anergy rather than stimulation. (3) In the presence of IFN-γ or IL-12 from the APC, T-cells differentiate into a memory (CD45RO+) TH1 (helper CD4+ cells) or TC1 (cytotoxic CD8+ cells) phenotype with expression predominantly of cytokines such as IL-2, IFN-γ, and TNF-α and the cytokine receptor IL-2R. IL-2 production in conjunction with IL-2R leads to autocrine proliferation of T-cells. This TH1/TC1 response is associated with cell- mediated immunity and autoimmune diseases such as psoriasis and rheumatoid arthritis.1 (4) In the presence of IL-10 or IL-4, T- cells differentiate into a memory (CD45RO+) TH2 (helper CD4+ cells) or TC2 (cytotoxic CD8+ cells) phenotype with expression of IL-4, IL-6 and IL-10. This TH2/TC2 response is associated with increased antibody production and antibody-mediated autoim- mune diseases such as atopic dermatitis.1 Activation and differentiation of T-cells induced by APC from the skin also induces ex- pression of CLA on the surface of the T-cells, which will enable them to return to the skin once maturation is complete. Further in- teraction between activated T-cells and endothelial cells include LFA-1 and VLA-4 with ICAM and VCAM, respectively. These interactions are important for the localization of the activated T-cells to sites of cutaneous inflammation.

CMAJ • JUNE 22, 2004; 170 (13) 1937 Walsh and Shear

on endothelial cells and activated keratinocytes.21 Although ther phase II testing. Similarly, the fusion protein early trials suggested that clinical remissions were generally CTLA4Ig, composed of the binding domain CTLA4 at- not sustained, bimonthly maintenance therapy was found tached to IgG1, blocks the T-AP dance by binding with to prevent lesion recurrence in the majority of responders.22 both CD-80 and CD-86 on APC. Again, preliminary stud- Several other agents designed to block costimulation ies suggested some efficacy in psoriasis; however, given the were investigated with respect to psoriasis, but such studies more global abrogation of T-cell responses with this med- were terminated at early phases because of either low effi- ication, its potential use in psoriasis is severely limited.24,25 cacy or potentially serious adverse events. Primatized mon- Methods designed to inhibit T-cell activation by induc- oclonal antibody IDEC-114 directed against CD-80 on ing T-cell anergy with CD4- or CD3-specific antibodies APC blocks costimulation with CD28 on T-cells, resulting have also had very limited applications to psoriasis. Nonde- in anergy rather than activation. Although preliminary pleting anti-CD4 antibodies humanized from either rats studies suggested that this approach had some effect on (hIgG1-CD4)26 or mice (orthoclone)27 and the humanized psoriasis,7,23 the level of clinical efficacy did not support fur- anti-CD3 antibody visilizumab28 induce T-cell anergy and

5

Epidermal hyperproliferation IL-12 4 1 IL-1 IL-6 Activated 2 IL-8 T-cell Epidermis T-cell Increased ICAM/ APC CD40 ICAM-1 VCAM expression Cytokines IFN-γ MHC II TC1 TNF-α Keratinocyte 3 VEGF

Cytokines Endothelial IL-8 IFN-γ cell proliferation TNF-α 6

TH1

Dermis 1 Recruitment of activated T-cells Activated T-cell Chesley Sheppard Fig. 6: The immunology of psoriasis. Immune activation occurs as APC process antigen, become activated, migrate to the local skin-draining lymph node and stimulate naïve T-cells to become activated memory T-cells expressing a TC1 or TH1 phenotype, which can then return to the skin via expression of CLA and LFA-1 (Figs. 4 and 5). (1) These activated T-cells express inflamma- tory cytokines TNF-α and IFN-γ which can (2) induce keratinocytes to produce adhesion molecules such as ICAM-1, costimula- tory molecules such as CD40 and MHC II molecules for antigen presentation, facilitating further T-cell/keratinocyte interactions. (3) TNF-α also induces keratinocytes to produce vascular endothelial cell growth factor (VEGF) which causes endothelial cell pro- liferation, increased ICAM/VCAM expression and subsequent increased recruitment of activated T-cells. Keratinocytes also pro- duce other proinflammatory cytokines such as IL-1 and IL-6 that are involved in regenerative responses. (4) Ongoing antigen stim- ulation between activated APC and T-cells can occur in the epidermis without the need for further APC migration to the lymph node. This is skewed to the TC1/TH1 phenotype by IL-12 produced by the APC. IFN-γ and TNF-α that are continually produced result in a regenerative phenotype of the keratinocytes, manifested as (5) epidermal hyperproliferation with elongation of the rete ridges, loss of the granular layer and retained nuclei in the stratum corneum (parakeratosis). (6) TNF-α also induces keratinocytes to produce IL-8 that is chemotactic for neutrophils.

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inhibit TH1 responses by unknown immune mechanisms. inhibited and down-regulated by exogenous TH2 cytokines These agents have yielded mixed results in early trials and (e.g., IL-4, IL-10 and IL-11). This also reduces proinflam- their future application to psoriasis is questionable.26–29 matory cytokines such as TNF-α. Clinical trials with both IL-432 and IL-1133 have yielded promising results, although T-AP 2: blocking proliferation and survival of continuous treatments may be necessary in order to activated T-cells achieve sustained improvement in psoriasis. Although early studies with IL-10 (Tenovil) suggested good efficacy,34,35 outcome was not considered sufficiently cost- Once the T-AP dance has started, subsequent T-cell effective to justify further development of this agent for proliferation can be inhibited either by blocking the growth treatment of people with psoriasis. signal required by the T-cells (IL-2 binding to the IL-2 re- ceptor [CD25]) or by directly killing activated T-cells with T-AP 4: blocking cytokines a toxin-ligated IL-2. Both of these treatments have demon- strated limited efficacy in psoriasis and are undergoing con- Finally, the outcome of the T-AP dance, the proinflam- tinued investigation.30,31 matory cytokine mediators, can be blocked with agents such as , , Abx-IL8 and HuZAF. The mouse T-AP 3: causing immune deviation chimeric antibody infliximab tightly binds both soluble and membrane bound forms of TNF-α.36 The fusion protein The third method in blocking the T-AP dance is im- Etanercept is comprised of two TNF-α receptors linked to α β 37 mune deviation (Table 1, Fig. 7). This approach exploits IgG1 and can bind only soluble TNF- and TNF- . Sus- the competition between TH1 and TH2 cytokines and their tained remissions with limited retreatments have been pos- 38 mutual down-regulation. Psoriatic TH1 cytokines secreted sible in open label trials with both of these agents. Al- by APC and activated T-cells (e.g., IFN-γ, IL-12) can be though inhibiting a late step in the psoriatic pathway, these

Table 1: Biologic agents currently under review for the treatment of psoriasis Mode of Biologic agent (brand name) Mechanism of action delivery Adverse effects Surveillance 1. Inhibition of T-cell activation and costimulation

Alefacept (Amevive) Fusion protein of LFA-3 tip and IgG1 binds to CD2 on IM Lymphopenia CD4 counts memory T-cell blocking costimulation and inducing T-cell Flu-like symptoms

apoptosis by NK cell bridging to IgG1 component. Siplizumab (Medi-507) to CD2 on T-cell blocking CD2-LFA-3 SC Lymphopenia CD4 counts costimulation and stimulating antibody-dependent memory Flu-like symptoms T-cell lysis. Efalizumab (Raptiva) Humanized antibody to CD11a component of LFA-1 on SC Flu-like symptoms Platelets T-cell which blocks binding to ICAMs on APC, endothelial Thrombocytopenia cells and activated keratinocytes. Rebound flares 2. Inhibition of T-cell proliferation and induction of T-cell destruction (Zenapax) Humanized antibody to Tac (p55) component of high affinity Flu-like symptoms None IL-2 receptor inhibiting IL-2 binding and T-cell proliferation.

Basiliximab (Simulect) Chimeric antibody to Tac (p55) component of high affinity IV Flu-like symptoms None IL-2 receptor inhibiting IL-2 binding and T-cell proliferation. infusion 3. Immune deviation

IL-4 (RhuIL-4) Recombinant TH2 cytokine used to skew TH1 cells to TH2 SC Flu-like symptoms None phenotype. Peripheral edema

IL-11 (Oprelvekin) Recombinant TH2 cytokine used to skew TH1 cells to TH2 SC Flu-like symptoms CBC phenotype. Arrhythmias platelets Peripheral edema 4. Cytokine blockade α Etanercept (Enbrel) Fusion protein of two TNF- receptors linked to IgG1 capable SC Tuberculosis None of reversibly binding to both TNF-α and TNF-β. activation Demyelinating disorders Infliximab (Remicade) Chimeric antibody to TNF-α capable of binding both soluble IV Tuberculosis None and membrane-bound forms. infusion activation Infusion reactions

Note: NK = , IM = intramuscular, SC = subcutaneous, ICAM = intercellular adhesion molecule, APC = antigen-presenting cells, IV = intravenous.

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anti-TNF-α agents have yielded the highest response rates ulomatous-type responses, and the TNF-α inhibitors in- among all of the biologics thus far investigated.36–38 fliximab and etanercept have been associated with tubercu- In contrast to TNF-α inhibitors, success with blocking losis infection or reactivation.41 Since both alefacept and other proinflammatory cytokines has been limited. Studies siplizumab result in antibody-mediated cytotoxicity of acti- with a fully humanized antibody to IL-8 (Abx-IL8) showed vated memory T-cells, treatment with these agents can only modest improvement in preliminary trials, suggesting cause a significant drop in T-cell counts.8,20 Furthermore, as that there might be significant redundancy in the role of this many of these agents are new on the market, the relevance cytokine in psoriasis pathogenesis.39 As a result, this agent is of potential associated adverse events such as demyelinating no longer in development for psoriasis. Novel humanized diseases has not yet been established.42 The safety and effi- antibodies to other inflammatory cytokines such as IFN-γ cacy of vaccinations is also uncertain with the immunosup- (HuZAF) are just beginning phase I clinical trials.40 pressive nature of these medications. Overall, the projected high cost poses the greatest potential limitation to the wide Precautions with biologic agents availability and accessibility of these agents.

Although these new biologic agents appear to act with Summary greater target specificity than the systemic immunosup- pressives that are currently available, questions remain re- The biologic agents represent a refined approach to tar- garding their safety in patients with ongoing or latent in- geted immunosuppression. At present, it is unclear why not fection, immunosuppression or malignancy. For example, all patients respond to each agent. It is likely that different TNF-α appears to be critical for the maintenance of gran- immune pathways may lead to the psoriatic phenotype and

2 T-cell inhibition or destruction 1 Inhibition of T-cell activation and co-stimulation

Antigen CD3 TCR MHC I/II Daclizumab CD4/CD8

Efalizumab T-cell LFA-1 ICAM-1 AP-cell CTLA-4 CD86 CD25 (IL-2R) CD28 Alefacept CD80 CD2 LFA-3 CD40LSiplizumab CD40 3 Cytokine blockade 4 Immune deviation

Infiximab Oprelvekin IL-12 TNF-α

IFN-γ TH2 Inhibition of TH1

Rhu IL-4 Etanercept IL-8 Chesley Sheppard Fig. 7: Biologic agents and their targets — The T-AP dance. Biologic agents either: (1) inhibit T-cell activation and costimulation (efalizumab, alefacept, siplizumab), (2) inhibit T-cell proliferation or induce their destruction (basiliximab, daclizumab), (3) block the effector cytokines (infliximab, etanercept) or (4) cause immune deviation (cytokines IL-11 [Oprelvekin] or IL-4). In the dia- gram, fusion proteins are red and antibody-based biologic agents are green. Binding of alefacept to CD2 previously up-regulated on memory effector T-cells not only blocks necessary signals for costimulation in the T-AP dance, but it also triggers memory T- cell apoptosis through binding of the Fc portion of the fusion protein to receptors on natural killer cells.8,18 Similar to alefacept, siplizumab also interacts with CD2, resulting in reduced memory effector T-cells, and may also produce prolonged clinical remis- sions.20 The chimeric basiliximab30 and the humanized daclizumab,31 both monoclonal antibodies raised against CD25 on acti- vated T-cells, limit survival of activated T-cells by causing antibody-induced cell lysis. The chimeric anti-TNF-α antibody inflix- imab tightly binds both soluble and membrane-bound forms of TNF-α and triggers complement-mediated lysis of TNF-α-expressing cells.36 The fusion protein etanercept is comprised of 2 TNF-α receptors linked to IgG1 and can bind soluble TNF-α and TNF-β.37 Although this complex is less stable than infliximab-TNF-α, both approaches have yielded significant reduc- tions in psoriasis in the majority of patients (Fig. 7, Table 1).36,37

1940 JAMC • 22 JUIN 2004; 170 (13) Psoriasis and the new biologics

thus different costimulatory molecules may have different 21. Gottlieb AB, Papp KA, Lynde CW, Carey W, Powers J, Rist TE, et al. Sub- cutaneous efalizumab (anti-CD11a) is effective in the treatment of moderate relevance to disease in a specific person. The diversity of to severe plaque psoriasis: pooled results of 2 phase III clinical trials [poster]. biologic agents becoming available to interrupt the T-AP American Academy of Dermatology meeting; 2002 Feb 22-27; New Orleans. 22. Gordon KB, Leonardi C, Harvey D, Powers J, Phillips H, Weinstein GD, et dance of psoriasis, together with their relative safety, may al. Continuous treatment improves outcomes in patients with moderate to se- yield additional effective treatment options for moderate to vere plaque psoriasis treated with subcutaneous (sc) efalizumab (anti-CD11a): results from the phase III trial ACD2058g [poster]. American Academy of severe psoriasis. Dermatology meeting; 2002 Feb 22-27; New Orleans. 23. Gottlieb AB, Lebwohl M, Totoritis MC, Abdulghani AA, Shuey SR, Romano This article has been peer reviewed. P, et al. Clinical and histologic response to single-dose treatment of moderate to severe psoriasis with an anti-CD80 . J Am Acad Der- From the Department of Medicine, Divisions of Dermatology (Walsh, Shear) and matol 2002;47:692-700. Clinical Pharmacology (Shear), Sunnybrook and Women’s College Health Sci- 24. Abrams JR, Lebwohl MG, Guzzo CA, Jegasothy BV, Goldfarb MT, Goffe ences Centre, University of Toronto, Toronto, Ont. BS, et al. CTLA4Ig–mediated blockade of T-cell costimulation in patients with psoriasis vulgaris. J Clin Invest 1999;103:1243-52. Competing interests: Neil Shear has acted as a paid clinical researcher for Serono, 25. Sayegh MH. Finally, CTLA4Ig graduates to the clinic. J Clin Invest 1999;103: Centocor, has received travel assistance to attend advisory board meeting with Bio- 1223-5. gen Idec and Amgen and is a principal in Ventana Clinical Research Corporation. 26. Isaacs JD, Burrows N, Wing M, Keogan MT, Rebello PR, Watts RA, et al. Humanized anti-CD4 monoclonal antibody therapy of autoimmune and in- Contributors: Neil Shear and Scott Walsh made substantial contributions to con- flammatory disease. Clin Exp Immunol 1997;110:158-66. ception and design and to the acquisition, analysis and interpretation of data. Scott 27. Gottlieb AB, Lebwohl M, Shirin S, Sherr A, Gilleaudeau P, Singer G, et al. Walsh drafted the article and Neil Shear revised it critically for important intellec- Anti-CD4 monoclonal antibody treatment of moderate to severe psoriasis tual content. Both authors approved the final version to be published. vulgaris: results of a pilot, multicenter, multiple-dose placebo-controlled study. J Am Acad Dermatol 2000;43:595-604. 28. 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Correspondence to: Dr. Neil Shear, Sunnybrook and Women’s 20. Papp K, Langley R, Matheson R, Dingivan C. Safety, tolerance, and biologi- cal activity of MEDI-507 (siplizumab) for the treatment of moderate to severe College Health Sciences Centre, Division of Dermatology, psoriasis [poster]. American Academy of Dermatology meeting. 2002 Febru- University of Toronto, 2075 Bayview Ave., Toronto ON ary 22-27; New Orleans. M4N 3M5; fax 416 480-6897; [email protected]

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